Broken Connections: The Evidence for Neuroglial Failure in ME/CFS

Abstract

In spite of decades of research, the pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is still poorly understood. Several pathomechanisms have been identified, yet, it remains unclear how they are related and which of them may be upstream or downstream.. In this paper, we present a theoretical strategy that may help clarify the causal chain of pathophysiological events in ME/CFS. We propose to focus on the common final histological pathway of ME/CFS and suggest to ask: Which cellular compartment may explain the pathological processes and clinical manifestations observed in ME/CFS? Any functional unit consistently identified through this search may then be a plausible candidate for further exploration.For this "histological" approach we have compiled a list of 22 undisputed clinical and pathophysiological features of ME/CFS that need to be plausibly and most directly explained by the dysfunctional cellular unit in question. For each feature we have searched the literature for pathophysiological explanations and analyzed if they may point to the same functional cellular unit.Through this search we have identified the CNS neuroglia - microglia and astroglia - as the one functional unit in the human body which may best explain all and any of the clinical and pathological features, dysfunctions and observations described for ME/CFS. While this points to neuroinflammation as the central hub in ME/CFS, it also points to a novel understanding of the neuroimmune basis of ME/CFS. After all, the neuroglial cells are now understood as the functional matrix of the human brain connectome which operates beyond and above specific brain centers, receptor units or neurotransmitter systems and integrates innate immune functions with CNS regulatory functions pertaining to autonomous regulation, cellular metabolism and the stress response.

The Pathobiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Case for Neuroglial Failure

“…In this review, we probed a hypothesis related to and building upon the latter category. Based on a previous summary of the potential role of CNS glia in ME/CFS ( Renz-Polster, 2021 ), we have analyzed the most salient and discriminating features of ME/CFS with the aim to determine if they may plausibly be explained by neuroglial dysfunction, i.e., pathological processes involving the glial cell populations, which we view as intricately linked.…”

“…To advance this quest, we have non-systematically reviewed the literature (without a specific timeframe) on the clinical and pathobiological features of ME/CFS ( Renz-Polster, 2021 ). From the material gathered, we hypothesize that a common mechanism underlying the pathobiological basis of ME/CFS may indeed be a regulatory CNS failure due to dysfunctional or pathologically reactive neuroglia, resulting in the typical multilevel clinical manifestations of ME/CFS.…”